RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
UHRF2 与 sumoylation 相关：评估其在结直肠癌免疫抑制中的作用及治疗潜力
英文原题：UHRF2 related to sumoylation : assessment of its role in immune suppression and therapeutic potential in colorectal cancer.
查看英文原题
UHRF2 related to sumoylation : assessment of its role in immune suppression and therapeutic potential in colorectal cancer.
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中文摘要
SUMO化是蛋白质的一种关键翻译后修饰。然而，SUMO化相关基因在调控肿瘤免疫微环境中的作用及其作为CRC治疗靶点的潜力仍不清楚。
我们整合了TCGA和GEO的转录组数据，鉴定出200个与预后相关的SUMO化相关基因。其中，选取了58个具有显著生存差异的基因，并将其分为三个不同的聚类。Cluster C患者预后最差，与肿瘤增殖增加和免疫反应减弱相关。LASSO联合随机生存森林（RSF）方法在十种机器学习算法中表现出最优性能，获得了最高的C-index（0.715）。随后，利用LASSO-RSF框架筛选出六个关键基因——SENP7、NUP85、UHRF2、BRCA1、TOPORS和SENP5——以构建 refined 预后模型。该模型表现出较高的预测准确性，1年、3年和5年总生存期AUC值分别为0.943、0.961和0.981。
此外，该模型得出的风险评分不仅与肿瘤转移和复发、晚期肿瘤分期及患者年龄显著相关，还与免疫细胞浸润、肿瘤突变负荷和抗癌药物敏感性显著相关。单细胞分析显示，核心基因UHRF2在CD8+耗竭T细胞中高表达，但在常规CD8+T细胞和NK 细胞中低表达。实验数据表明，UHRF2在CRC中上调，并与不良预后相关。沉默UHRF2可显著抑制体外肿瘤细胞的增殖和迁移，以及体内肿瘤生长。
总之，基于SUMO化相关基因得出的预后模型对患者结局显示出稳健的预测准确性。UHRF2与免疫抑制相关并促进CRC进展，使其成为CRC中有前景的治疗靶点。
展开英文摘要原文
SUMOylation is a critical post-translational modification of proteins.
However, the roles of SUMOylation-related genes in regulating the tumor immune microenvironment and their potential as therapeutic targets in CRC remain unclear.
We integrated transcriptomic data from TCGA and GEO to identify 200 SUMOylation-related genes associated with prognosis. Among these, 58 genes exhibiting significant survival differences were selected and classified into three distinct clusters. Cluster C patients have the worst prognosis, linked to increased tumor proliferation and weakened immune responses.
The LASSO combined with Random Survival Forest (RSF) approach demonstrated optimal performance in ten machine learning algorithms, yielding the highest C-index (0. 715). Subsequently, six key genes—SENP7, NUP85, UHRF2, BRCA1, TOPORS, and SENP5—were selected using the LASSO-RSF framework to develop a refined prognostic model. This model demonstrated high predictive accuracy, with 1-, 3-, and 5-year overall survival AUC values of 0. 943, 0. 961, and 0. 981, respectively.
Furthermore, the risk score derived from the model was significantly correlated not only with tumor metastasis and recurrence, advanced tumor stage, and patient age, but also with immune cell infiltration, tumor mutational burden, and sensitivity to anticancer drugs.
Single-cell analysis revealed that the core gene UHRF2 is highly expressed in CD8 + exhausted T cells, but exhibits low expression in conventional CD8 + T cells and natural killer cells. Experimental data demonstrated that UHRF2 was upregulated in CRC and linked to poor prognosis. Silencing UHRF2 markedly inhibited both proliferation and migration of tumor cells in vitro, as well as tumor growth in vivo.
In conclusion, the prognostic model derived from SUMOylation-related genes demonstrates robust predictive accuracy for patient outcomes. UHRF2 is associated with immunosuppression and promotes CRC progression, positioning it as a promising therapeutic target in CRC.
论文信息
- 作者
- Huang M、Qin Y、Yang Q、Chen X、Chen K
- 第一作者单位
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.China
- 通讯作者单位
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China. yinyuedegushi@126.com.China
- 期刊
- BMC cancer2026 Feb 27
- 原文标识
- PubMed 41761142 · DOI 10.1186/s12885-026-15727-7
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